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WO 2009/018233 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 5 February 2009 (05.02.2009) PCT WO 2009/018233 Al (51) International Patent Classification: QUART, Barry [US/US]; 3273 Violet Ridge, Encinitas, AOlN 41/06 (2006.01) A61K 31/18 (2006.01) CA 92024 (US). MINER, Jeffrey, N. [US/US]; 4572 Pauling Ave., San Diego, CA 92122 (US). (21) International Application Number: PCT/US2008/071392 (74) Agents: HADDACH, Aubrey, A. et al; Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA (22) International Filing Date: 28 July 2008 (28.07.2008) 94304-1050 (US). (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (26) Publication Language: English CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (30) Priority Data: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 11/830,733 30 July 2007 (30.07.2007) US LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, 61/034,466 6 March 2008 (06.03.2008) US MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, 61/034,464 6 March 2008 (06.03.2008) US RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, 61/044,886 14 April 2008 (14.04.2008) US TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicant (for all designated States except US): ARDEA BIOSCIENCES, INC. [US/US]; 4939 Directors Place, (84) Designated States (unless otherwise indicated, for every San Diego, CA 92121 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (75) Inventors/Applicants (for US only): VERNIER, European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Jean-michel [FR/US]; 24831 Cutter, Laguna Niguel, CA FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, 92677 (US). ROWLINGS, Colin, Edward [US/US]; NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, 1908 Paxton Way, Encinitas, CA 92024 (US). GI- CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). RARDET, Jean-luc [FR/US]; 17 Open View Lane, Aliso Viejo, CA 92656 (US). DIMOCK, Stuart [US/US]; Published: 24144 Graystone Drive, Lake Forest, CA 92630 (US). — with international search report (54) Title: DERIVATIVES OF N-(ARYLAMINO) SULFONAMIDES INCLUDING POLYMORPHS AS INHIBITORS OF MEK AS WELL AS COMPOSITIONS, METHODS OF USE AND METHODS FOR PREPARING THE SAME (57) Abstract: This invention concerns N-(2-arylamino) aryl sulfonamide compounds which are inhibitors of MEK including crys- talline polymorphic forms which exhibit a specific powder x-ray diffraction profile and/or a specific differential scanning calorimetry profile. This invention also concerns pharmaceutical compositions comprising the compounds described herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer, hyperprolif- erative diseases and inflammatory conditions. The invention also concerns methods of making the compunds and compositions described herein. DERIVATIVES OF N-(ARYLAMINO) SULFONAMIDES INCLUDING POLYMORPHS AS INHIBITORS OF MEK AS WELL AS COMPOSITIONS, METHODS OF USE AND METHODS FOR PREPARING THE SAME CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Ser. Nos. 61/044,886, filed April 14, 2008, 61/034,466 filed March 6, 2008, and 61/034,464 filed March 6, 2008, each of which is hereby incorporated by reference in the entirety. This application also claims priority to US Application Serial No. 11/830,733, filed July 30, 2007, which claims the benefit of U.S. Provisional Application Ser. No. 60/833,886 filed July 28, 2006 and of International Application Ser. No PCT/US2006/028326 filed July 21, 2006 as a continuation-in-part application, each of which is hereby incorporated by reference in the entirety. International Application Serial No PCT/US2006/028326 also claims priority to U.S. Provisional Application Ser. Nos. 60/701,814 filed July 21, 2005; 60/706,719 filed August 8, 2005, and to 60/731,633 filed October 28, 2005, each of which is hereby incorporated by reference in the entirety. FIELD OF THE INVENTION This invention concerns N-(2-arylamino) aryl sulfonamide compounds which are inhibitors of MEK including crystalline polymorphic forms which exhibit a specific powder x-ray diffraction profile and/or a specific differential scanning calorimetry profile. This invention also concerns pharmaceutical compositions comprising the compounds described herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer, hyperproliferative diseases and inflammatory conditions. The invention also concerns methods of making the compunds and compositions described herein. BACKGROUND OF THE INVENTION Oncogenes ~ genes that contribute to the production of cancers ~ are generally mutated forms of certain normal cellular genes ("proto-oncogenes"). Oncogenes often encode abnormal versions of signal pathway components, such as receptor tyrosine kinases, serine-threonine kinases, or downstream signaling molecules. The central downstream signaling molecules are the Ras proteins, which are anchored on the inner surfaces of cytoplasmic membranes, and which hydrolyze bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When activated by a growth factor, growth factor receptors initiate a chain of reactions that leads to the activation of guanine nucleotide exchange activity on Ras. Ras alternates between an active "on" state with a bound GTP (hereafter "Ras.GTP") and an inactive "off state with a bound GDP. The active "on" state, Ras.GTP, binds to and activates proteins that control the growth and differentiation of cells. For example, in the "mitogen-activated protein kinase (MAP kinase) cascade," Ras.GTP leads to the activation of a cascade of serine/threonine kinases. One of several groups of kinases known to require a Ras.GTP for their own activation is the Raf family. The Raf proteins activate "MEKl" and "MEK2," abbreviations for mitogen-activated £RK- activating Mnases (where ERK is extracellular signal-regulated protein kinase, another designation for MAPK). MEKl and MEK2 are dual-function serine/threonine and tyrosine protein kinases and are also known as MAP kinase kinases. Thus, Ras.GTP activates Raf, which activates MEKl and MEK2, which activate MAP kinase (MAPK). Activation of MAP kinase by mitogens appears to be essential for proliferation, and constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, as by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. The interaction of Raf and Ras is a key regulatory step in the control of cell proliferation. To date, no substrates of MEK other than MAPK have been identified; however, recent reports indicate that MEK may also be activated by other upstream signal proteins such as MEK kinase or MEKKl and PKC. Activated MAPK translocates and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as EBc-I and Sapla, leading to the enhanced expression of genes such as that for c-fos. Once activated, Raf and other kinases phosphorylate MEK on two neighboring serine residues, S218 and S222 in the case of MEKl . These phosphorylations are required for activation of MEK as a kinase. In turn, MEK phosphorylates MAP kinase on two residues separated by a single amino acid: a tyrosine, Y185 and a threonine, T183. MEK appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Two factors — MEK's unusual specificity and its requirement for a strong interaction with MAP kinase prior to phosphorylation —suggest that MEK's mechanism of action may differ sufficiently from the mechanisms of other protein kinases as to allow for selective inhibitors of MEK. Possibly, such inhibitors would operate through allosteric mechanisms rather than through the more usual mechanism involving blockage of an ATP binding site. Thus, MEKl and MEK2 are validated and accepted targets for antiproliferative therapies, even when the oncogenic mutation does not affect MEK structure or expression. See, eg., U.S. Patent Publications 2003/0149015 by Barrett et al. and 2004/0029898 by Boyle et al. Several examples of l-substituted-2(p-substituted-phenylamino)-aryl inhibitors of MEK have been reported. U.S. Patent Nos. 6,440,966 and 6,750,217 and corresponding publication WO 00/42003 described carboxylic and hydroxamic acid esters and N-substituted amide derivatives of sulfonamide-substituted-2(4-iodophenylamino)-benzoic acid esters and N-substituted benzamides as functioning as MEK inhibitors. The sulfonamide may also be N-substituted. U.S. Patent 6,545,030 and corresponding publication WO 00/42029 describe MEK inhibitors that are 1- heterocyclyl-2(4-iodophenylamino)-benzene, where the heterocycle is a five-membered nitrogen-containing ring such as pyrazole, triazole, oxazole, isoxazole, and isoxazolinone. The more recent U.S. Patent Publication 2005/004186 describes related compounds in which the 4-iodo substituent of the '030 patent is replaced by a very broad genus of moieties including alkyl, alkoxy, acyloxy, alkenyl, carbamoyl, carbamoylalkyl, carboxyl, carboxylalkyl, N- acylsulfonamido, and others. U.S. Patent 6,469,004 and corresponding publication WO 00/42022 describe carboxylic and hydroxamic acid esters of a group of heterocyclo-condensed phenylene compounds, i.e., benzimidazoles, benzooxazoles, benzothiazoles, benzothiadiazoles, quinazolines, etc.
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